Atroposelective Formal [2 + 5] Macrocyclization Synthesis for a Novel All-Hydrocarbon Cyclo[7] Meta-Benzene Macrocycle

A novel axially chiral all-hydrocarbon cyclo[7] (1,3-(4,6-dimethyl)benzene (CDMB-7) was designed and synthesized using atroposelective[2 + 5] cyclization through Suzuki–Miyaura coupling. CDMB-7 adopts an irregular bowl-like shape with C2 symmetry and exhibits two diastereoisomers in its crystallographic structure. The conformational isomers of CDMB-7 racemates remain stable at high temperatures (393 K). High-performance liquid chromatography (HPLC) confirmed that a single chiral isomer will spontaneously undergo racemization within 30 min at room temperature. This finding opens up possibilities for achieving adaptive chirality in all-hydrocarbon cyclo[7] m-benzene macrocycles.

Cyclo-meta-phenylenes (CMPs), characterized by a representative macrocycle [37,38], have attracted widespread interest due to their simple composition and unique structure.So far, due to the lack of involved synthesis and modification strategies, few all-hydrocarbon as-prepared CMPs and related derivatives CDMB-8 [39] (Figure 1A) have been reported.Herein, we build a new, all-hydrocarbon cyclo [7] (1,3-(4,6-dimethyl)benzene) (CDMB-7) that exists in C 2 symmetry.Two non-enantiomeric isomers of CDMB-7 can be generated simultaneously, and still maintain the stability of the configuration at high-temperatures (393 K), without causing conversion due to external stimuli.

Results
The synthesis of CDMB-7 is shown in Figure 1B.Briefly, the Suzuki-Miyaura coupling "[2+5]" cyclization between boronylated dimer 1 [40] and dibrominated pentamer 2 afforded the target macrocycle CDMB-7 in a yield of 26%.Dibrominated pentamer 2 was generated from the reported work [39]; then, with the varieties of chiral ligands involved and through controlling the process of asymmetric cyclization [41][42][43], unfortunately, the obtained pure products are still racemic mixtures.Its structure was subsequently confirmed by single crystal X-ray diffraction.
The [Pd], base, and solvent effects in the cyclization from 1, 2, and 3 are explored for the reaction optimization (Table 1).The highest 26% yield is achieved using Cs2CO3 under Ar and PhMe (Note: the reaction solvents are all analytical reagents (ARs)).

Results
The synthesis of CDMB-7 is shown in Figure 1B.Briefly, the Suzuki-Miyaura coupling " [2 + 5]" cyclization between boronylated dimer 1 [40] and dibrominated pentamer 2 afforded the target macrocycle CDMB-7 in a yield of 26%.Dibrominated pentamer 2 was generated from the reported work [39]; then, with the varieties of chiral ligands involved and through controlling the process of asymmetric cyclization [41][42][43], unfortunately, the obtained pure products are still racemic mixtures.Its structure was subsequently confirmed by single crystal X-ray diffraction.
The [Pd], base, and solvent effects in the cyclization from 1, 2, and 3 are explored for the reaction optimization (Table 1).The highest 26% yield is achieved using Cs 2 CO 3 under Ar and PhMe (Note: the reaction solvents are all analytical reagents (ARs)).
It is applied to preliminary single chiral isomer exploration by adding additional chiral ligands under the optimized condition.This showed that using (R)-(+)-2,2 ′ -Bis(diphenylphosphino)-1,1 ′ -binaphthyl or (S)-(+)-2,2 ′ -Bis(diphenylphosphino)-1,1 ′ -binaphthyl, the yields are 43% and 40%, respectively (Table 2, entry 1, 2).However, the addition of other chiral phosphine ligands did not have a significant promotional effect on the yield, as shown in Table 2. Hence, it suggests that the (S)-binaphthyl ligands positively influence the enhancement of the reaction yield by generating a bidentate coordination reaction intermediate in the same orientation as 2. Thus, both (R)-BINAP and (S)-BINAP can produce the racemic form of CDMB-7 with a high yield.and through controlling the process of asymmetric cyclization [41][42][43], unfortunately, the obtained pure products are still racemic mixtures.Its structure was subsequently confirmed by single crystal X-ray diffraction.
The [Pd], base, and solvent effects in the cyclization from 1, 2, and 3 are explored for the reaction optimization (Table 1).The highest 26% yield is achieved using Cs2CO3 under Ar and PhMe (Note: the reaction solvents are all analytical reagents (ARs)).Moreover, the HPLC-confirmed target macrocycles, obtained after the reaction of all chiral ligands involved, were found to be racemic.It indicates that the introduction of chiral ligands did not effectively regulate the chirality of products.The rigidity of fragments 1, 2 was probably the main factor in generating the single chiral isomer.

Discussion
The 1 H NMR spectrum of CDMB-7 (produced through the above synthetic process) recorded at 273 K in tetrachloroethane-d 2 (TCE-d 2 ) is characterized by six signals for the benzene ring protons that appear in a 1:4:3:2:2:2 ratio (Figure 2a).Seven groups of signals are seen (appearing as three overlapping peaks) corresponding to the meso-methyl groups.In addition, 21 signals are also seen in the 13 C NMR spectrum (Figure S10, ESI).The findings mentioned above help us prove that CDMB-7 adopts a fixed structure with C 2 symmetry in TCE-d 2 .
According to the analysis of NMR, the two-dimensional spectrum revealed that the benzene ring interactions between adjacent hydrogen-hydrogen and remote hydrogenhydrogen in the macrocyclic molecule CDMB-7 are relatively weak (Figure 2b).The HSQC and HMBC two-dimensional spectrum have not been detected.Thus, it confirmed that there is almost no interaction between the inside carbon and hydrogen atoms of CDMB-7 macrocycle, also explaining the macrocycle structure's existence as individual units.The variable temperature 1 H NMR showed some shifts in specific signals seen upon heating at 283-393 K temperature range, the whole spectroscopic peak of the NMR recorded at 283 K was retained (Figure 2c).It indicates that the conformer of C 2 -CDMB-7 exists in a de-symmetrization shape-persistent nature at high temperatures.According to the analysis of NMR, the two-dimensional spectrum revealed that the benzene ring interactions between adjacent hydrogen-hydrogen and remote hydrogenhydrogen in the macrocyclic molecule CDMB-7 are relatively weak (Figure 2b).The HSQC and HMBC two-dimensional spectrum have not been detected.Thus, it confirmed that there is almost no interaction between the inside carbon and hydrogen atoms of CDMB-7 macrocycle, also explaining the macrocycle structure's existence as individual units.The variable temperature 1 H NMR showed some shifts in specific signals seen upon heating at 283-393 K temperature range, the whole spectroscopic peak of the NMR recorded at 283 K was retained (Figure 2c).It indicates that the conformer of C2-CDMB-7 exists in a de-symmetrization shape-persistent nature at high temperatures.

Materials and Methods
We have achieved the separation of the single chiral isomer with diastereoselectvity of CDMB-7, generating peaks with an area ratio of 1:1 in chromatographic analysis column AD-H (mainly filled with silica surface covalently bonded cellulose-tri (3,5-dimethylphenylcarbamoyl) and the factor of chiral separation reaches 2 in HPLC (Figure 3a).Then, it successfully separated two single conformational isomers of the diastereoselective C2-CDMB-7 (separate yield < 5%, ee: 85%, 83%) using n-hexane and methanol (99/1, v/v) as the mobile phase through AD chromatographic preparation column at 30 °C.
However, it was further investigated when the two diastereoselective separated chiral isomer solutions were allowed to stand at room temperature for 30 min; the respective samples were injected again, and the signals of the two sets of chromatographic peaks showed consistency with the determination results of the racemic mixture in HPLC.
The initial crystallographic data obtained through chiral mode X-ray diffraction analysis (Figure 3b) showed two diastereoselective isomers of CDMB-7 rapidly reaching racemization in solution.It is postulated that the absence of strong polar or bulky substituents, other than the methyl group, in the molecular structure of CDMB-7 contributes to

Materials and Methods
We have achieved the separation of the single chiral isomer with diastereoselectvity of CDMB-7, generating peaks with an area ratio of 1:1 in chromatographic analysis column AD-H (mainly filled with silica surface covalently bonded cellulose-tri (3,5-dimethylphenylcarbamoyl) and the factor of chiral separation reaches 2 in HPLC (Figure 3a).Then, it successfully separated two single conformational isomers of the diastereoselective C 2 -CDMB-7 (separate yield < 5%, ee: 85%, 83%) using n-hexane and methanol (99/1, v/v) as the mobile phase through AD chromatographic preparation column at 30 • C.
However, it was further investigated when the two diastereoselective separated chiral isomer solutions were allowed to stand at room temperature for 30 min; the respective samples were injected again, and the signals of the two sets of chromatographic peaks showed consistency with the determination results of the racemic mixture in HPLC.
The initial crystallographic data obtained through chiral mode X-ray diffraction analysis (Figure 3b) showed two diastereoselective isomers of CDMB-7 rapidly reaching racemization in solution.It is postulated that the absence of strong polar or bulky substituents, other than the methyl group, in the molecular structure of CDMB-7 contributes to this conversion.This construction results in a shallow energy barrier for the configurational interconversion of its chiral isomers.Solvent interaction further facilitates this process, allowing the molecules to attain an energetic equilibrium easily.
Consequently, the single chiral species transform into their enantioselective images (mirror isomer), culminating in forming a stable racemic mixture in CDMB-7 solid phase.The findings of this research suggest that the nature of the functional group substitutions in CDMB-7, as well the selection of solvent, are likely the primary determinants influencing its enantioselective reactivity.On the other hand, the meso-dimethyl multi-aromatic ring units of C 2 -CDMB-7 and its irregular twisted conformation have the characteristic of available enantiomerization for racemization.
This study establishes a foundation for further investigation of the self-adaptive chirality of C 2 -CDMB-7.C 2 -CDMB-7 can responsively alter its chiral conformation in reaction to diverse external stimuli, such as pressure, solvents, and guest molecules.This adaptive shift in chiral configuration or conformation elicits distinctive chiral responses.Furthermore, we try to synthesize a novel chiral pharmaceutical derived from the CDMB-7 scaffold, tailored to interact with the humors, blood, or additional biological mediators within the organism.This interaction aims to effectuate a conformational shift in the target drug molecule, enhancing its lesion-specific therapeutic potency, thereby, eradicating associated pathologies.Moreover, we strive to attain the precise modulation of CDMB-7 analog adaptive chiral entities to guarantee their conformational transition is exclusive to particular solvent systems.Such specificity would enable these molecules to discriminate selectively against distinct ions, chiral diminutive molecules, or chiral moieties in a solution, thus augmenting the enantioselectivity of chiral recognition.

Conclusions
In conclusion, we have demonstrated a novel axially chiral cyclo [7] (1,3-(4,6-dimethyl) benzene (CDMB-7), synthesized through atroposelective Suzuki-Miyaura [2 + 5] cyclization in 43% yield.This protocol offers an economical and straightforward approach for directly synthesizing all-hydrocarbon odd-numbered multi-aromatic macrocycles.Analytical studies, including X-ray, NMR, and HPLC, identified that the atroposelectivity primarily originates from the rigidity of the as-prepared fragments, and the conformation of C 2 -CDMB-7 can undergo spontaneous "racemization".These insights pave the way for further investigations into the self-adaptive chirality of C 2 -CDMB-7 and its potential application in dynamic chiral recognition, detection, and luminescence.

Supplementary Materials:
The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules29143363/s1,The detailed synthetic procedures of new compounds, experimental figures, UV-vis and fluorescence spectra, X-ray crystal structure, and analytical data (PDF).

Table 1 .
Optimization of reaction conditions a .

Table 1 .
Optimization of reaction conditions a .

Table 1 .
Optimization of reaction conditions a .

Table 2 .
Exploration of chiral phosphine ligand a .